The Challenge of Preparing and Testing Combinatorial Compound Libraries in the Fast Lane, at the Front End of Drug Development

Abstract

Combinatorial Compound Libraries (CCL) are at the front end of the development of new chemical entities. They are the result of a pragmatic, goal-oriented attitude, which emphasizes the discovery side of research activities. The odds to bump into a discovery, however, are pushed to the extreme with rigorously planned rationales. The CCL field has its origin in peptide chemistry but is migrating into general organic chemistry. The incentive is the coveted goal to be able to prepare large libraries of 'small molecules'. Efforts are directed towards an expansion of the repertoire of high yield reactions on solid phase, in order to readily access semi-rigid globular ligands. The CCL approach comes with its own strategies to provide a massive increase of compound evaluations by taking full advantage of the integrated preparation process with the option to control the physical format of compound ensembles or to classify them into defined subpopulations. A noticeable impact on the drug discovery process is expected. The libraries' preparation and evaluation principles are briefly discussed in this essay.